Dipeptidyl peptidase-IV (DPPIV) is a kind of serine protease that specifically hydrolyzes the dipeptide-X-Pro (X may be any amino acid) from the free N terminus of a polypeptide chain.
Glucose-dependent insulinotropic hormone (incretin; GLP-1, Glucagon-Like Peptide-1 and GIP; Glucose-dependent Insulinotropic Polypeptide), which is secreted postprandially from the intestinal tract, is quickly degraded and inactivated by this DPPIV Suppressing this degradation of GLP-1 by DPPIV enhances the action of incretin (GLP-1 and GIP), and facilitates insulin secretion from pancreatic β-cells due to glucose stimulus. It has been shown that, as a result, postchallenge hyperglycemia is improved in oral glucose tolerance tests (see Non-patent document 1). Furthermore, it has also been shown that GLP-1 is involved in suppressive effects on appetite and food intake, and also in β cell protection based on its promotional effect on pancreatic β cell differentiation and growth.
Therefore, DPPIV inhibitors can be expected to serve as useful therapeutic and preventive agents against diseases involving GLP-1 and GIP, such as obesity and diabetes.
As shown below, a relationship has been reported between various diseases, including diabetes, and DPPIV DPPIV inhibitors can therefore be expected to become therapeutic agents for such diseases.
(1) Preventive and therapeutic agents for AIDS (see Non-patent document 2),
(2) preventive and therapeutic agents for osteoporosis (see Non-patent document 3),
(3) preventive and therapeutic agents for intestinal disorders (see Non-patent document 4),
(4) preventive and therapeutic agents for hyperlipidemia, diabetes, and obesity, (see Non-patent documents 5 and 6),
(5) preventive and therapeutic agents for angiogenesis (see Non-patent document 7),
(6) preventive and therapeutic agents for infertility (see Patent document 1),
(7) preventive and therapeutic agents for inflammatory diseases, autoimmune diseases, and chronic rheumatoid arthritis (see Non-patent document 8), and
(8) preventive and therapeutic agents for cancer (see Non-patent documents 9 and 10),
(9) preventive and therapeutic agents for multiple sclerosis (see Non-patent document 11)
Although a number of DPPIV inhibitors are known (see Patent documents 2-11), DPPIV inhibitors comprising a fused 1,3-dihydroimidazole ring are not known.
[Non-patent document 1]
Diabetologia 1999 November, 42(11): 1324-31
[Non-patent document 2]
Science 1993, 262: 2045-2050
[Non-patent document 3]
Clinical chemistry 1988, 34: 2499-2501
[Non-patent document 4]
Endocrinology 2000, 141: 4013-4020
[Non-patent document 5]
Diabetes 1998, 47: 1663-1670,
[Non-patent document 6]
Life Sci 2000, 66(2): 91-103
[Non-patent document 7]
Agents and actions 1991, 32: 125-127
[Non-patent document 8]
The Journal of Immunology 2001, 166: 2041-2048
[Non-patent document 9]
Br J Cancer 1999 March, 79(7-8): 1042-8
[Non-patent document 10]
J Androl 2000 March-April, 21(2): 220-6
[Non-patent document 11]
The Journal of Immunology 2001, 166: 2041-48
[Patent document 1]
WO 00/56296
[Patent document 2]
US Patent Application No. 2001020006
[Patent document 3]
U.S. Pat. No. 6,303,661
[Patent document 4]
U.S. Pat. No. 6,011,155
[Patent document 5]
U.S. Pat. No. 5,543,396
[Patent document 6]
WO 02/02560
[Patent document 7]
WO 00/34241
[Patent document 8]
WO 99/61431
[Patent document 9]
WO 99/67279
[Patent document 10]
WO 97/40832
[Patent document 11]
WO 95/29691
[Patent document 12]
WO 02/068420
As described above, compounds with DPPIV-inhibiting activity useful as pharmaceutical agents are being earnestly sought. However, a compound with excellent DPPIV-inhibiting activity, which is also very useful as a clinically effective pharmaceutical, has yet to be discovered. Thus, an objective of the present invention is to search for and find compounds with DPPIV-inhibiting activity that can be used as preventive or therapeutic agents for the above-mentioned diseases (particularly diabetes and such).